Solid dosage form refers essentially to pharmaceutical drug products in the form of tablets, capsules, powders, granules, lozenges and suppositories containing an active drug component or a mixture of active drug component (Active Pharmaceutical Ingredient) and non-drug components (excipients).
The scale-up of solid dosage form would be better appreciated if one understands the Pilot scale up techniques used in pharmaceutical manufacturing and general considerations during pilot plant scale up.
Contents
Typical unit operations involved in the production of solid dosage forms
1. Material Handling
In large scale operations, mechanical means of handling materials such as mechanical devices for lifting and tilting drums and more sophisticated methods of handling materials such as screw feed systems, vacuum loading systems, and metering pumps become necessary unlike in the laboratory where materials are simply scooped, dumped or poured by hand. Any material handling system used must deliver the accurate amount of the ingredient to the intended destination with minimal losses. Lengthy transfer lines may result in material loss, for which these must be compensation.
2. Dry Blending
All the ingredients (excipients and active ingredients) are meant to be free of lumps and agglomerates prior to the dry blend. Failure to remove or break up all agglomerates could cause flow problems through the equipment creating a non-reproducible compression. Screening and/ or milling of the ingredients prior to mixing should be done to make the process more reliable and reproducible. Powders to be used for encapsulation or for granulation prior to tableting must be well blended to ensure good drug distribution. Inadequate blending could result in discrete portions of the batch being either high or low in potency.
3. Granulation
Wet granulation can be achieved using sigma blade or heavy duty planetary mixers. Production equipment of this type equipped with large motors of 7 to 10 horse power can process up to 100 to 200kg of material. The granulation time and the amount of granulation fluid required relative to that used in experimental laboratory trials can be affected by the weight of the material and the large shear forces generated by these powerful units. Wet granules can also be prepared using tumble blenders equipped with high-speed chopper blades. High shear mixers are more effective in densifying light powders. However they demand large amounts of energy. They also have a limited load size. Some equipment combine this high shear mixing action required for good densification with the advantages, of high speed choppers which break up agglomerates and ensure uniform distribution of the granulating fluid and a more controlled granule size.
There are also multi-functional processors which are unit capable of performing all the functions required to prepare a finished granulation such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in single equipment.
The advantage of such equipment in scale up of product is the space and man power requirements. The viscosity of the granulating solution can be adjusted if the problem of binder addition to the powders being processes is anticipated. The binding agent sometimes imparts considerable viscosity to the granulating solution, making the transfer of the fluid by either pumping or pouring difficult. One way of solving this problem is to disperse some or the entire binding agent in the dry powder prior to granulating and the granulating liquid containing any remaining binder can thus be easily pumped and metered into the batch during granulation.
Some granulation when prepared in production size equipment take on a dough like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.. This can be accomplished by passing the wet mass through an oscillating type granulator with a suitable screen or a hammer mill with a suitably large screen.
4. Drying
During scale up of this operation, the granulation bed depth should be carefully controlled and the drying process monitored by the use of moisture and or temperature probes in the granulation. The important factors to consider as part of scale up of an oven drying operation are air flow, air temperature, and the depth of the granulation in the trays. The drying process will be inefficient if the granulation bed is too dense. Migration of the dye to the surface of the granule may also occur if soluble dyes are involved.
The drying process can also be monitored by frequent multi-point sampling of the granulation for moisture content throughout the drying phase. Drying times at specified temperatures and airflow rates must be established for each product and for each particular oven load.
In the scale up of a fluidized bed drying operation, the optimum load must first be established. Also the rate of air flow and inlet air temperature as well as the humidity of the incoming air must be established, since all these affect the drying time. The main advantage of the fluidized bed dryers is the reduction in drying time. Fluidized bed drying times are usually lesser than 1 hour, compared to the 8hr or more of the conventional ovens. However, the scale up of a fluidized bed drying operation is more involving than scale up of a circulating hot air oven process. For instance, if the air drawn from outside the plant is not conditioned, the large seasonal variations in temperature and humidity that may exist can alter the drying process.
5. Reduction of Particle Size
In the laboratory, hand screening or short duration handling with a small scale milling equipment is used to obtain the desired particle size distributions prior to compression or encapsulation. When such a process is increased in capacity to accommodate large, high-speed presses with more elaborate feed systems, it is vital that the equipment chosen yield the desired output while controlling the particle size and size distribution, which are important characteristics of a granulation.
Particle size reduction of the dried granulation of production size batches can be achieved by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device or a screening device. Oscillating granulators work well when the oversized portions of the granulation including lumps or agglomerates are not too hard. Care must be taken not to overfeed the equipment to avoid the production of excessive number of fines.
Hammer mills are also frequently used to mill dried granulation to a specified size distribution. They have a rapid output and the particle size distribution can be controlled by varying the screen size, the speed of the mill, the type and number of hammer, blades used and the rate of material feed.
The most suitable milling equipment for granule particle size reduction can be chosen by first determining the characteristics of the unmilled granulation and then selection of equipment to produce the particle size distribution necessary for the best performance during the compression or encapsulation stages.
Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness and tablet content uniformity. For instance a granulation with too large particle Sizes and insufficient fines is unable to fill the die cavities uniformly during compression. The weight of the tablets will therefore fluctuate considerably.
As part of the scale up of a milling or sieving operation, the lubricants and glidants which are added directly to the final blend (in the laboratory), are now added to the dried granulation during the sizing operation. This is done because some of these additives especially magnesium stearate, tend to form clumps when added in large quantities to the granulation in a blender.
6. Blending
Attention should be given to the scale up of this operation so that equipment of the right design is used, with blender loads, mixing speeds and mixing times properly established. This is vital because the type of blending equipment used in production operations are different from that used in the laboratory especially in size. A good understanding of the characteristics of the material to be blended helps to make a full scale production processing operation successful and more efficient. For instance, a product with fragile particles or agglomerates can be easily abraded or crushed resulting in an excessive amount of fines.
These fines could mix improperly to cause flow problems, fill weight and content uniformity problems. In any blending operation, both segregation and mixing occur simultaneously. Both processes depend on the particle size, shape, hardness, density and dynamics of the mixing action. Hence the characteristics of the different powders in the blend must be known and the cause of segregation understood, so that the blending operation cause optimized to produce a uniform blend.
7. Granulation Handling and Feed System
Studies need to be undertaken to determine the effect of additional handling (in large-scale operations) on the content uniformity of a drug and on the particle size distribution. Segregation due to static charges built up during the mechanical handling of the granulation can lead to problems with material flow through tablet press hoppers and feed frames. This flow problem can lead to poor control of tablet weight, thickness, hardness and ultimately poor content uniformly.
In the laboratory, the handling of a finished granulation can be a simple operation such as hand scooping of the material from a drum into the press hopper. For large operations, a sophisticated, automated handling system using mechanical systems can be employed to convey the granulation.
8. Compression
Prolonged trial runs at press speeds equal to that to be used in normal production should be tried when evaluating the compression characteristics of a particular formulation. This is done to identify potential problems such as sticking to punch surfaces tablet hardness, capping and weight variation. These pre-production trials in the pilot plant are vital to identify these problems early in the scale up process so that changes can easily be made. Such changes will be more difficult during later production runs, because marketing requirements may make it difficult to interrupt production schedules in order to modify the formulation. Compression of a granulation on a high speed tablet press is the ultimate test of a tablet formulation and granulation process.
The tablet press performs the following functions during compression;
- Filling of empty die cavity with granulation
- Compression of granulation
- Ejection of the tablet from the die cavity
The design of the tablet press determines the manner of accomplishment of these functions. Machine design also determines the usable range of compression forces at which the machine can safely operate and the press speed at which output can be optimized without negative impact on tablet quality.
Reference
Ramasubramaniyan P., Shibin raj C., Nagarajan P., Sherly D., Subramanian L., and Solairaj P. (2014). Pilot Scale-up Techniques for Solid Dosage Form: An Overview for Tablets. World Journal of Pharmaceutical Research. 3(8): 925-931.
The title of this article is Scale-up of Solid Dosage Forms